Evaluation of The Metabolic Syndrome Criteria And Body Composition in Ambulatory Children with Epilepsy UsingSodium Valproate and Carbamazepine In Southern Iran: A Case-Control Study

Objectives Previous studies in adults with epilepsy revealed a higher prevalence of metabolic syndrome, resulting in cerebrovascular and cardiovascular events. However, there is insufficient data about body composition and metabolic syndrome in children, especially in the Middle Eastern region. We aimed to investigate metabolic syndrome criteria and body composition in ambulatory children with Epilepsy in Southern Iran. Material & Methods Seventy seven epileptic children with an average age of 11.4 ± 3.2 years and their age-gender-matched controls were included in this study. Anthropometric data, lipid profile, blood glucose, and blood pressure were checked. Body composition was also evaluated by Hologic system dual-energy X-ray absorptiometry. Results The prevalence of metabolic syndrome as well as the fat mass index in patients were higher than the controls, and p values are 0.032 and 0.012, respectively. Moreover, the lean mass with Bone Mineral Content (BMC) index was detected lower than the controls (P= 0.017). Regarding drugs consumption, serum triglyceride and the blood pressure in patients who receiving carbamazepine was higher than the control individuals with P = 0.019, Beta = 0.379 and P = 0.016, Beta = -0.26, respectively. Fat mass index was also higher in patients using sodium valproate (P = 0.031, Beta = 0.238). Conclusion Our study revealed that children with epilepsy are more prone to metabolic syndrome and higher body fat mass. Therefore, early diagnosis and prevention of metabolic syndrome criteria in patients with epilepsy, With performing regular exercise and having a healthy diet should be encouraged in these children.


Introduction
Cardiovascular diseases are one of the most important leading causes of morbidity and mortality worldwide (1). Metabolic syndrome (MS) is defined as a group of metabolic risk factors, including glucose intolerance, dyslipidemia, hypertension, and central obesity as the main risk factors for cerebrovascular and cardiovascular events (2). Urbanization, fast food, and sedentary lifestyle have led to an increase in the prevalence of obesity and metabolic disturbances in developing countries children (3,4), which was reported to be a significant economic burden on public health (5).
In some of the previous reports, epilepsy was shown to be associated with a higher risk of cardiovascular diseases (6)(7)(8)(9)(10)(11). One study amongst adults with epilepsy showed that the prevalence of metabolic syndrome in sodium valproate and carbamazepine treated patients in Estonia was 20% and 40%, respectively (6). In addition, another study in India showed that 29.5% of young adults with epilepsy had metabolic syndrome 7 . To the best of our knowledge, there are a limited number of studies regarding metabolic syndrome in children with seizure (10,12). For instant, it has been reported that in Chinese children with obesity and epilepsy the prevalence of metabolic syndrome was 47.2%, which was not much more than the non-epileptic children with obesity (10). Another study among

Study Design
The present case-control study was performed in pediatric neurology clinics affiliated to Shiraz

Pubertal Stage And Blood Pressure
An expert pediatric endocrinologist evaluated the weight, height, waist circumference and pubertal stage of all participants. Weight was measured while the child was dressed a light clothing on a standard balance (Seca, Germany) and rounded to the nearest 0.1 kg. Height was measured while the child stood without shoes near a wall-mounted meter and rounded to the nearest 0.5 cm. Waist circumference was taken with a measuring tape at the midway level between the lateral rib margin and the iliac crest while the child stood upright and rounded to nearest 0.5 cm. BMI was also calculated by the following formula: Puberty was evaluated according to the tanner standard system (13). Tanner stage 1 was considered as pre pubertal stage, tanner stages 2 or 3 as early pubertal and tanner stage and 4 or 5 as late pubertal stages (13,14). Arterial blood pressure was measured twice with 30 min interval through the standard auscultatory method using a sphygenomanometer, with suitable cuff size. The mean of two blood pressures was considered as the recorded blood pressure.

Body Composition
Body composition was measured through a Hologic system dual -energy X-ray absorptiometry (DXA) (Discovery QDR, USA). The interpretation of body composition was done using the normative database of Hologic System DXA for children ages 5-23 (15). Fat mass index was also selected as a criteria for body fat composition (16).

Definition of Metabolic Syndrome
Metabolic syndrome was defined according to the latest International Diabetes Federation (IDF) consensus statement (17). Impaired glucose tolerance was defined as fasting glucose between 100-125 mg/dl; Hypertriglyceridemia defined as serum triglycerides higher than 90 th percentile for age and gender specific range; low HDL-C was defined as HDL-C ≤ 10 th percentile for age and gender specific range; hypertension was defined as blood pressure greater than 90 th percentile for age, gender, and height specific range; and abdominal obesity was defined as waist circumference more than 90 th percentile for age, gender and race specific range (17). Diagnosing the metabolic syndrome requires the presence of central obesity, plus any two of the other four factors.

Statistical Analysis
Statistical analysis was done using SPSS software, version 25. Data were indicated as mean ± SD and percentage. Student t-test and Mann-Whitney test were used to analyze quantitative data, and chisquare and fisher exact test were used to compare qualitative data between the two groups. Pearson correlation test was used to analyze two quantitative variables. Multiple regression test was used to evaluate the effect of some associated factors on metabolic, and body composition criteria. P-values Iran J Child Neurol. Summer 2020 Vol. 14 No. 3 less than 0.05 were considered to be statistically significant.

Results
This study included 77 epileptic children with average age 11.4 ± 3.2 years and 77 healthy age and gender-matched controls; half of each group were male. Prevalence of generalized tonic-clonic convulsions, partial seizure, and absence seizures were 71%, 16.9% and 2.6%, respectively. The most used anticonvulsant drugs were sodium valproate (72%) and carbamazepine (37%).

Discussion
The present study showed that the prevalence of metabolic syndrome in children with seizure disorder was more than the healthy children (7.8% vs 1.1%, p-value = 0.032, 95% confidence interval: -0.127_ -0.005). In addition, we showed that fat mass index in children with epilepsy was higher than the healthy children who did not affected by epilepsy; However, lean + Bone mineral content in children with epilepsy was lower than their healthy controls. Amongst metabolic criteria, hypertriglyceridemia and central obesity were higher in children with epilepsy. In addition, we revealed that carbamazepine usage was associated with higher TG and higher blood pressure, but sodium valproate usage was linked to a higher fat mass index. Previous reports in adults showed a high prevalence of metabolic syndrome among patients with epilepsy (7), ranging from 29.5% in Indian young adults to 20% in Estonia (6) as well as 43% in overweight patients with epilepsy in Italy (8). Difference in the prevalence might be due to patient's selection criteria, such as age, weight, anticonvulsants medications, and race (6)(7)(8). Limited number of studies have been performed regarding the prevalence of metabolic syndrome in children with epilepsy. They showed a relative higher rate of hyperlipidemia in Indian children using sodium valproate, (12) and 47% prevalence of metabolic syndrome in Chinese patients with epilepsy and obesity using sodium valproate (10).
As far as we know, the present study was the first to have evaluated a relatively large number (77) of ambulatory children with epilepsy compared to healthy controls. The present study also showed that 7.8% of the children had IDF criteria of metabolic syndrome, which was higher than healthy children. In patients with epilepsy, a sedentary lifestyle and anti-epileptic drugs (AEDS) can lead to obesity and metabolic syndrome (18,19).